We have developed the first SIV/macaque model of HAART therapy in HIV-infected individuals. These animal studies will answer questions about HIV infection and pathogenesis that cannot be answered by studying HIV infection in humans. Animal experiments are central to study tissue reservoirs and to examine the relafionship between peripheral immune responses and SIV-associated neurological disease. Blood, CSF and/or tissues from infected macaques are used by each Project in the Program. The animal studies are designed to address the following questions: To what level does SIV still replicate and how much proviral DNA is present in peripheral and neurological fissues during apparently effective HAART therapy? Is it possible to further reduce the level of virus replication to be undetectable even by the most sensitive assays? Does eariier initiation of HAART therapy reduce the number of cells trafficking to the CNS and the levels of virus in tissue reservoirs? Does eariier initiation of HAART better preserve peripheral immune system function, preventing the effects of persistent immune activation that results in loss of control over virus and eventually resulting in inflammafion and degenerafion in the nervous system? Macaques will be inoculated with SIV using our well-characterized accelerated, consistent SIV/macaque model in which over 90% of inoculated macaques develop encephalitis by 3 months p.i. Macaques will be treated with Tenofovir (RT inhibitor), Atazanavir (protease inhibitor). Saquinavir (protease inhibitor), and Merck 206DA (integrase inhibitor) beginning at 4, 12 or 28 days after virus inoculation. Some animals will be subsequenfiy treated with a test compound designed to purge tissue reservoirs. Other groups of animals will be used as controls for the above studies. Blood and CSF will be sampled every week for the first 6 weeks after virus inoculation and every two weeks thereafter until euthanasia. Addditional macaques will be used for pharmacokinetic studies to determine the appropriate dose and frequency to achieve effective levels of a test compound that will be used to purge viral in plasma and to determine the extent to which the drug crosses the blood-brain barrier. These macaques will not be euthanized and will be used in later experiments.